Aromatic Drug Molecules Research Articles

Facile incorporation of dispersed fluorescent carbon nanodots into mesoporous silica nanosphere for pH-triggered drug delivery and imaging

Dispersed incorporation of functional nanoparticles into ordered mesopores to exert their synergistic properties has shown a promising application, but proved to be a challenging task. Herein, a facile strategy based on solid-phase transformation of the template into polymer-coated carbonaceous nanodots (pCNDs) is used for direct synthesis of multifunctional mesoporous silica nanospheres (MFMSNs) incorporated with dispersed fluorescent carbon nanodots. The homogeneous pCNDs incorporated into mesoporous silica nanospheres (MSNs) can simultaneously act as the nontoxic fluorescence probe for highly efficient fluorescence imaging and also anchoring sites for anticancer drug loading. On the basis of the special hydrophobic π–π/electrostatic interaction between the confined pCNDs in MFMSNs and the aromatic drug molecules, MFMSNs could also function as an advanced drug carrier for pH-triggered drug release. The very simple strategy suggests new insights for synthesizing multifunctional mesoporous nanomaterials and extends the biomedical functions of traditional MSN-based nanovehicles for future biomedical applications.

Pegylated folate and peptide-decorated graphene oxide nanovehicle for in vivo targeted delivery of anticancer drugs and therapeutic self-monitoring

This work reports a graphene oxide-based nanovehicle with conjugation of pegylated folate for targeted delivery of anticancer drugs and fluorescein-labeled peptide for therapeutic self-monitoring in vitro and in vivo. The nanovehicle could absorb hydrophobic and aromatic drug molecules with high loading capacity and efficiency of more than 1.7mgmg−1 and 90%, respectively. MTT and flow cytometric assays demonstrated that the drug-loaded nanovehicle could specifically transport and release the drugs into the folate receptor high-expressed cancer cells, which ensured a high therapeutic efficiency to cancer cells and prevented the injury to normal cells. Moreover, confocal fluorescence imaging confirmed that the drug-induced cancer cell death could be visualized with the light-up fluorescence of fluorescein activated by caspase-3. The targeted delivery of drug and self-evaluation of therapeutic efficacy were further successfully realized by living imaging in tumor-bearing mice, which broaden the applications of this theranostic system in vivo and may offer new opportunities for precise cancer treatment.

Iridium-Catalyzed C–H Activation and Deuteration of Primary Sulfonamides: An Experimental and Computational Study

Iridium-catalyzed C–H activation and ortho-hydrogen isotope exchange is an important technology for allowing access to labeled organic substrates and aromatic drug molecules and for the development of further C–H activation processes in organic synthesis. The use of [(COD)Ir(NHC)Cl] complexes (NHC = N-heterocyclic carbene) in the ortho-deuteration of primary sulfonamides under ambient conditions is reported. This methodology has been applied to the deuteration of a series of substrates, including the COX-2 inhibitors Celecoxib and Mavacoxib, demonstrating selective complexation of the primary sulfonamide over a competing pyrazole moiety. The observed chemoselectivity can be reversed by employing more encumbered catalyst derivatives of the type [(COD)Ir(NHC)(PPh3)]PF6. Computational studies have revealed that, although C–H activation is rate-determining, substrate complexation or subsequent C–H activation can be product-determining depending on the catalyst employed.

Interceptor effect of C60 fullerene on the in vitro action of aromatic drug molecules.

C60 fullerenes are spherical molecules composed purely of carbon atoms. They inspire a particularly strong scientific interest because of their specific physico-chemical properties and potential medical and nanotechnological applications. In this work we are focusing on studying the influence of the pristine C60 fullerene on biological activity of some aromatic drug molecules in human buccal epithelial cells. Assessment of the heterochromatin structure in the cell nucleus as well as the barrier function of the cell membrane was performed. The methods of cell microelectrophoresis and atomic force microscopy were also applied. A concentration-dependent restoration of the functional activity of the cellular nucleus after exposure to DNA-binding drugs (doxorubicin, proflavine and ethidium bromide) has been observed in human buccal epithelial cells upon addition of C60 fullerene at a concentration of ~10(-5 )M. The results were shown to follow the framework of interceptor/protector action theory, assuming that non-covalent complexation between C60 fullerene and the drugs (i.e., hetero-association) is the major process responsible for the observed biological effects. An independent confirmation of this hypothesis was obtained via investigation of the cellular response of buccal epithelium to the coadministration of the aromatic drugs and caffeine, and it is based on the well-established role of hetero-association in drug-caffeine systems. The results indicate that C60 fullerene may reverse the effects caused by the aromatic drugs, thereby pointing out the potential possibility of the use of aromatic drugs in combination with C60 fullerene for regulation of their medico-biological action.

Complexation of C60 Fullerene with Aromatic Drugs

The contributions of various physical factors to the energetics of complexation of aromatic drug molecules with C(60) fullerene are investigated in terms of the calculated magnitudes of equilibrium complexation constants and the components of the net Gibbs free energy. Models of complexation are developed taking into account the polydisperse nature of fullerene solutions in terms of the continuous or discrete (fractal) aggregation of C(60) molecules. Analysis of the energetics has shown that stabilization of the ligand-fullerene complexes in aqueous solution is mainly determined by intermolecular van der Waals interactions and, to lesser extent, by hydrophobic interactions. The results provide a physicochemical basis for a potentially new biotechnological application of fullerenes as modulators of biological activity of aromatic drugs.

Interactomics of Blebbistatin

Photoreactive molecules like aryl azides play important role in life sciences, as practical tools to achieve precisely timed covalent cross-links between ligands and targets. Since the azido group is small, stable and biologically inert, azido-modified aromatic drug molecules can keep their original pharmacological activity. By photoactivating of such modified molecules in vivo, both their strong and weak partners can be captured. Moreover, applying the azidated drug in a concentration range and utilizing proteomic tools the apparent binding constants of protein-ligand interactions can be determined.We have developed a new and simple technique to azidate aromatic drug molecules in an easy two step reaction. Using our method we have synthesized azidoblebbistatin which is a new derivative of blebbistatin, the most widely used myosin inhibitor. In the absence of UV irradiation azidoblebbistatin and blebbistatin exhibits identical inhibitory properties. Using UV light azidoblebbistatin can be covalently crosslinked to myosin whereas the unbound inhibitor molecules become inactive. Using Dictyostelium discoideum cell lysate we performed interactomic investigation to identify the previously unknown targets of blebbistatin utilizing the self- fluorescence of azidoblebbistatin. Since the crosslinking was performed applying increasing concentration of azidoblebbistatin, densitometry of the fluorescent spots resulting from gelelectrophoresis revealed the apparent binding constant of azidoblebbistatin. In case of myosin II it was the exact value as measured in in vitro tests. With this technique the strongest interactant was found to be myosin II (EC50=5 μM) while eight weak partners (EC50>30 μM) were also detected including vacuolar H+-ATPase (EC50=50 ± 31 μM), malate dehydrogenase (EC50=55 ± 17 μM) and elongation factor 1α (EC50>100 μM).

1H NMR study of the complexation of aromatic drugs with dimethylxanthine derivatives

With an aim of searching efficient interceptors of aromatic drugs, the self- and hetero-association of dimethylxanthine derivatives with different structures, selected according to Strategy 1 (variation of the position of methyl groups) and Strategy 2 (variation of the length of -(CH2)(n)-COOH group), with aromatic drug molecules: Ethidium Bromide, Proflavine and Daunomycin, were studied using H-1 NMR spectroscopy. It was found that the association proceeds in a form of stacking-type complexation and its energetics is relatively independent on the structure of the dimethylxanthines. However, on average, the dimethylxanthines possess higher hetero-association constant and, hence, higher interceptor ability as compared to the trimethylxanthine, Caffeine, used during the past two decades as a typical interceptor molecule. (C) 2011 Elsevier B.V. All rights reserved.

Calculation of the electrostatic charges and energies for intercalation of aromatic drug molecules with DNA

AbstractIn this work, we analyzed the influence of the charge model on the magnitudes of atomic charges and electrostatic energies for the binding of aromatic drug molecules with DNA. The dependence of the charge and energy on the level of theory (HF, DFT (B3LYP), MP2, semi‐empirical methods), basis set (STO‐3G, 3‐21G, 6‐31G, 6‐31G*, 6‐31G**), method of charge computation (Mulliken, Natural Population Analysis, CHelpG, Merz–Kollman), and force field charge (CHARMM27, AMBER99) has been tracked for typical aromatic drugs of different structure and charge state. Recommendations and restrictions have been formulated for the use of particular approaches in charge/electrostatic energy calculations. © 2009 Wiley Periodicals, Inc. Int J Quantum Chem, 2011

Partition of thermodynamic energies of drug–DNA complexation

We report a computation methodology, which leads to the ability to partition the Gibb's free energy for the complexation reaction of aromatic drug molecules with DNA. Using this approach, it is now possible to calculate the absolute values of the energy contributions of various physical factors to the DNA binding process, whose summation gives a value that is reasonably close to the experimentally measured Gibb's free energy of binding. Application of the methodology to binding of various aromatic drugs with DNA provides an answer to the question "What forces are the main contributors to the stabilization of aromatic ligand-DNA complexes?"

Nano-graphene oxide for cellular imaging and drug delivery

Two-dimensional graphene offers interesting electronic, thermal, and mechanical properties that are currently being explored for advanced electronics, membranes, and composites. Here we synthesize and explore the biological applications of nano-graphene oxide (NGO), i.e., single-layer graphene oxide sheets down to a few nanometers in lateral width. We develop functionalization chemistry in order to impart solubility and compatibility of NGO in biological environments. We obtain size separated pegylated NGO sheets that are soluble in buffers and serum without agglomeration. The NGO sheets are found to be photoluminescent in the visible and infrared regions. The intrinsic photoluminescence (PL) of NGO is used for live cell imaging in the near-infrared (NIR) with little background. We found that simple physisorption via pi-stacking can be used for loading doxorubicin, a widely used cancer drug onto NGO functionalized with antibody for selective killing of cancer cells in vitro. Owing to its small size, intrinsic optical properties, large specific surface area, low cost, and useful non-covalent interactions with aromatic drug molecules, NGO is a promising new material for biological and medical applications.

Structural and thermodynamic analysis of the hetero-association of theophylline with aromatic drug molecules

The hetero-association of theophylline (THP) with other biologically-active aromatic molecules ( e.g. the anti-cancer drugs daunomycin and novantrone, the antibiotic norfloxacin, the vitamin flavin-mononucleotide and two mutagens ethidium bromide and proflavine) has been studied by NMR in aqueous-salt solution (0.1 M Na-phosphate buffer, p D 7.1). It was found that THP shows an essentially similar hetero-association ability as caffeine (CAF) towards aromatic drugs, except for novantrone (NOV), which has much less affinity to THP than CAF as a result of energetically unfavourable orthogonal orientation of the chromophores of THP and NOV in the hetero-complex.

Quantitation of the molecular mechanisms of biological synergism in a mixture of DNA-acting aromatic drugs

It is suggested that the widely reported biological synergism of a mixture of DNA-targeting aromatic drug molecules both in vivo and in vitro can be explained, in part, at the molecular level by competition between two basic mechanisms: the ‘interceptor’ (hetero-association between Drug1 and Drug2) and ‘protector’ mechanisms (complexation of Drug1 and Drug2 on DNA-binding sites). In the present work a complete analytical methodology has been developed to quantify these processes, providing an estimate of the relative importance of the interceptor/protector mechanisms using just a set of equilibrium association constants. The general methodology may be applied to other molecules with receptors for aromatic drugs.

On the origin of the decrease in stability of the DNA hairpin d(GCGAAGC) on complexation with aromatic drugs

Molecular dynamics simulations of drug–DNA complexes have been carried out in order to explain the experimentally observed decrease in thermal stability of the DNA hairpin d(GCGAAGC) on binding the aromatic drug molecules, daunomycin, ethidium bromide, novantrone and proflavine. This complexation behavior is in contrast to the stabilizing effect of the same aromatic drug molecules on DNA duplexes. Analysis of the energy parameters and the hydration properties of the complexes shows that the main factor correlating with the decrease in melting temperatures of the drug–hairpin complexes is the number of water bridges, with a reduction of at least 40% on ligand binding.

Self-association of the antitumour agent novatrone (mitoxantrone) and its hetero-association with caffeine

The self-association of the antitumour drug, novatrone, NOV (mitoxantrone) and its hetero-association with caffeine (CAF) have been investigated by 1D and 2D 500 MHz 1H NMR spectroscopy. Two-dimensional homonuclear correlation NMR spectroscopy (2D TOCSY and 2D ROESY) has been used for complete assignment of proton signals and for a qualitative analysis of the mutual arrangements of the aromatic drug molecules in the aggregates. The structural and thermodynamical parameters of molecular self- and hetero-association of the aromatic compounds have been determined from measurements of the NMR chemical shifts of the drug protons as a function of concentration and temperature. The self-association of NOV has been analysed using both the indefinite cooperative and non-cooperative models, and the hetero-association of NOV and CAF has been analysed in terms of a statistical-thermodynamical model, in which molecules form indefinite aggregates for both self- and hetero-association. The magnitudes of parameters (equilibrium reaction constants, enthalpy (ΔH) and entropy (ΔS)) have been calculated for self-association of NOV and its complexation with CAF; at 318 K the equilibrium constant for self-association of NOV is 12400 (±4000) l mol−1 and for hetero-association with CAF is 256 (±30) l mol−1. The most favourable structures of the NOV dimer and the 1∶1 NOV–CAF hetero-association complexes have been determined from the calculated limiting values of the induced chemical shifts of the drug protons.

1H NMR investigation of self-association of aromatic drug molecules in aqueous solution. Structural and thermodynamical analysis

Self-association of aromatic drug molecules, proflavine (PF), Acridine Orange (AO), ethidium bromide (EB) and actinomycin D (ActD), in aqueous salt solution has been studied by one- and two-dimensional 500 MHz 1H NMR spectroscopy. 2D-COSY and 2D-NOESY measurements were used for complete assignment of proton signals of EB and ActD in solution and for a qualitative determination of their self-association, i.e. the mutual arrangement of the drug molecules in the complexes. Concentration and temperature dependences of proton chemical shifts of the drugs have been measured. Experimental results have been analysed using indefinite non-cooperative and cooperative models of molecular self-association, enabling the determination of equilibrium reaction constants, parameters of cooperativity, the thermodynamical parameters (enthalpy and entropy) of the self-association reactions and the limiting values of drug proton chemical shifts in the complexes. The most favourable dimer structures of PF, AO, EB and ActD have been constructed using calculated values of induced chemical shifts of drug protons in conjunction with intermolecular NOEs. The results show that the drug chromophores have an antiparallel orientation in all the dimers studied.